Gene transfer (also known as gene therapy) is a relatively new technology for the treatment of rare genetic disorders and common multifactorial diseases. Eukaryotes are equipped to protect the genome and oppose the expression of abnormal or foreign transcription units. As a result, a transgene construct introduced into a cell can trigger transcriptional silencing wherein, after a period of expression, expression of the coding sequence in the transgene construct declines to undetectable levels without the loss of the construct.
The expression of therapeutic coding sequences can be augmented by including genetic control elements, such as promoters, that control expression of the gene in response to systemically administered drugs. In other strategies, vectors are engineered to include cis-modifications of retroviral vector sequences, for example mutations of virus silencer elements, in order to prevent silencing of the transgene (Ellis et al., Curr Gene Ther., 5:367-73, 2005). Vectors can also be designed to include strong positive regulatory elements and insulators, and to avoid the use of non-mammalian reporter genes. However, gene silencing (the conversion of an actively expressed gene, or coding sequence, to a non-expressed gene that occurs without a change in the primary DNA sequence) continues to be a major impediment in gene therapy and a need exists for developing methods of inhibiting gene silencing.